Metabolism of natural and synthetic corticosteroids in relation to their effects on mouse fetuses
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Abstract:
14C-glucose uptake by mouse fetuses was reduced by doses of dexamethasone, 200 mug or more, which over 2 days caused fetal death. Uptake by strain C57B1/6J greater than A/J greater than SWV. Corticosterone or cortisol, 4 mg, caused neither reduced uptake nor fetal death. These differences occurred despite similar maternal hyperglycemia in all cases. Recovery of 3H-steroid after 15 min, total and unchanged steroid per gram fetal tissue was: corticosterone 1.7 and 0.3%; dexamethasone 0.12 and 0.06% of the dose. Rapid metabolism of corticosterone apparently prevents accumulation in fetal tissue sufficient to evoke a response under these conditions.
Insights
Dexamethasone reduced fetal glucose uptake and caused fetal death in mice, unlike corticosterone or cortisol. This suggests dexamethasone
Area of Science:
- Reproductive biology
- Developmental toxicology
- Endocrinology
Background:
- Glucocorticoids are critical for fetal development.
- Maternal hyperglycemia can impact fetal glucose metabolism.
- Differential sensitivity of fetal tissues to steroids is poorly understood.
Purpose of the Study:
- To investigate the effects of dexamethasone, corticosterone, and cortisol on fetal glucose uptake in mice.
- To compare the accumulation and metabolism of these steroids in fetal tissues.
- To determine the relationship between steroid exposure, fetal glucose uptake, and fetal viability.
Main Methods:
- Mice were administered varying doses of dexamethasone, corticosterone, or cortisol.
- 14C-glucose uptake by fetuses was measured.
- 3H-steroid recovery and metabolism in fetal tissues were analyzed.
- Fetal viability was assessed over a 2-day period.
Main Results:
- Dexamethasone (≥200 µg) significantly reduced fetal glucose uptake and led to fetal death.
- Corticosterone and cortisol (4 mg) did not affect glucose uptake or cause fetal death.
- Strain differences in glucose uptake were observed (C57B1/6J > A/J > SWV).
- Rapid metabolism of corticosterone limited its accumulation in fetal tissues compared to dexamethasone.
Conclusions:
- Dexamethasone exhibits potent fetotoxicity by impairing glucose uptake, likely due to its slower metabolism and greater fetal tissue accumulation.
- Corticosterone's rapid metabolism prevents significant accumulation and subsequent toxicity under these experimental conditions.
- These findings highlight the importance of steroid metabolism in determining developmental toxicity.